Because infection with avipox viruses does not produce new virions, the degree of neutralizing

antibodies generated following mammalian infection is quite low. This allows viral particles to persist for a longer period of time and lifescience express foreign transgenes resulting in significantly enhanced T-cell immunity. Further studies in animal models suggested that heterologous prime-boost vaccination schedules using 2 different poxvirus vectors expressing tumorantigen and costimulatory factors induced stronger immune Inhibitors,research,lifescience,medical responses against foreign antigens compared with single-agent immunization protocols. A TRIad of COstimulatory Molecules (TRICOM) consists of co-stimulatory molecules including intercellular adhesion molecule (ICAM)-1, B7.1, and leukocyte function-associated antigen-3 (LFA-3). Preclinical studies using TRICOM were previously demonstrated to be superior to those containing only 1 or 2 of the costimulatory molecules. Following a phase I trial, a phase II study randomized 32 chemonaive patients with progressive metastatic CRPC into 1 Inhibitors,research,lifescience,medical of 4 cohorts.29 All cohorts received initial vaccine consisting of priming rV-PSA-TRICOM followed by monthly boosting with rF-PSATRICOM (Prostvac®-VF; Therion Biologics, Cambridge, MA). Patients randomized to cohort 1 received vaccine alone, cohort

2 received vaccine with recombinant GM-CSF protein, and cohorts 3 and 4 received Inhibitors,research,lifescience,medical vaccine with 2 different doses of fowlpox-GM-CSF. PSA-survival for the majority of patients exceeded predicted survival. The median survival was 26.3 months, whereas the nomogram-predicted median survival was 17.4 months. Eleven of 32 patients were alive with

a median follow-up of 44.6 months. Twelve patients (37.5%) Inhibitors,research,lifescience,medical displayed some decrease of PSA, and 14 of 30 (46.7%) evaluable patients displayed decreases in PSA velocity. Immune responses to PSA were demonstrated by ELISpot (IFN-γ secretion in vitro by T cells in response to PSA peptide). The ability of patients to mount a ≥ 6-fold increase in T-cell responses was associated with an increase in survival. In a recently reported double-blind, Inhibitors,research,lifescience,medical randomized, phase II trial of patients enrolled between November Physiological Reviews 2003 and July 2005, 122 patients with chemonaive minimally symptomatic metastatic CRPC, Gleason score ≤ 7, and no visceral metastasis were treated with Prostvac-VF or placebo in a 2:1 ratio.30 The primary endpoint was progression-free survival (PFS) defined as 2 new lesions on bone scan or Response Evaluation Criteria In Solid Tumors (RECIST)-defined progression. PFS was similar in the 2 groups (P = .56) and originally, the trial was reported as negative. However, with greater follow-up, Prostvac-treated patients experienced a significantly greater median survival (25.1 vs 16.6 months, P = .0061) (Table 1). Additionally, Prostvac-VF patients had a better 3-year survival (30% vs 17%).